Low-dose Intravenous Infusion Research Articles

Assessment of the effect of unfractionated heparin administered either by intravenous infusion vs. subcutaneous injection on heparin-binding protein, and plasminogen activator inhibitor-1 in critically ill septic patients: a randomized controlled trial.

The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine’s molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

A randomised comparative study of erector spinae plane block versus low-dose ketamine-dexmedetomidine intravenous infusion as intraoperative opioid-free analgesia for modified radical mastectomy.

Opioid-sparing analgesia for acute postoperative pain after breast cancer surgery is crucial due to opioid-related side effects. The utilisation of erector spinae plane block and low-dose intravenous ketamine-dexmedetomidine are widely recognised as non-opioid analgesic methodologies. The objective of this study was to conduct a randomised trial to examine the analgesic efficacy of both approaches while minimising the use of opioids. Seventy-two female patients scheduled for unilateral modified radical mastectomy were recruited. They were allocated randomly to Group ESPB, which received ipsilateral ultrasound-guided erector spinae plane block by 20 mL bupivacaine 0.5% at the level of T5 after induction of general anaesthesia, and Group Ket-Dex, which received intravenous (IV) bolus 0.25 mg/kg of ketamine and 0.5 µg/kg of dexmedetomidine, followed by an IV infusion of 0.25 mg/kg of ketamine and 0.3 µg/kg of dexmedetomidine per hour. Total postoperative morphine consumption (24 h) was the primary outcome. The secondary outcomes were pain scores over 24 hours during rest, duration of analgesia, isoflurane consumption, time to awakening, postoperative nausea and vomiting (PONV), and postoperative serum cortisol level. The postoperative morphine consumption over 24-hour in Group ESPB was 3.26 mg (0-6.74) versus 2.35 mg (2.08-4.88) in Group Ket-Dex (P = 0.046). Group Ket-Dex had lower pain scores at rest, longer analgesia duration, longer awakening time, and lower postoperative serum cortisol levels. Intravenous low-dose ketamine-dexmedetomidine infusion intraoperatively with inhalational-based general anaesthesia provides superior opioid-sparing analgesia to that of ESPB in patients undergoing unilateral non-reconstructive modified radical mastectomy, with less postoperative opioid consumption and stress response.

Analgesic Effect of Intraoperative Intravenous S(+)-Ketamine During Total Knee Arthroplasty Surgery: Study Protocol for a Randomized Controlled Clinical Trial.

Total knee arthroplasty (TKA) is currently the main treatment for end-stage knee disease. The number of cases of TKA in China increased from 53,880 in 2011 to 374,833 in 2019, representing a 5.9-fold increase. Moderate to severe pain often occurs after TKA, which seriously affects postoperative rehabilitation, patient satisfaction, and overall outcome. Multimodal analgesia is considered the ideal solution. Adequate postoperative analgesia can not only reduce pain, opioid consumption, and, consequently, opioid-related adverse events, but can also reduce the length of hospital stay and costs and improve rehabilitation and patient satisfaction. Effective multimodal pain management in the early postoperative period is essential for anesthesiologists. Additional studies have demonstrated that a low-dose intravenous infusion of ketamine can be administered as an adjuvant drug to alleviate acute postoperative pain. Therefore, we aim to appraise the efficacy and safety of intraoperative intravenous injection of S(+)-ketamine to relieve acute pain after TKA in older patients. This is a protocol for a randomized, placebo-controlled trial. A total of 144 participants aged 65 years and older undergoing TKA will be randomly allocated into the S(+)-ketamine and placebo groups in a 1:1 ratio. S(+)-ketamine or the placebo will be intravenously administered at 0.3 mg/kg/h during the operation by anesthesiologists. Blinded evaluation by trained investigators will be completed at 2 hours, 24 hours, and 48 hours after surgery. The primary outcome measure will be the numeric rating scale score at rest and movement at 24 hours after surgery. The secondary outcomes will include the numeric rating scale scores at rest and movement at 2 hours and 48 hours after surgery, the number of patients who require additional analgesics during the first 48 hours after operation, the total consumption of opioids or nonsteroid anti-inflammatory drugs during the first 48 hours after operation, and adverse events at 2, 24, and 48 hours after operation. The protocol was registered at Clinical Trials.gov on February 26, 2022. It was performed in accordance with the approved guidelines and regulations of the participating institutions. Recruitment began in April 2022. Data collection is expected to conclude in September 2024. Study completion is expected in December 2024. A randomized, controlled, clinical study was designed to observe the analgesic effect of intraoperative intravenous administration of a lower dose of S(+)-ketamine (0.3 mg/kg/h) in older patients after TKA surgery. The protocol will appraise the efficacy and safety of intraoperative intravenous injection of S(+)-ketamine to relieve acute pain after TKA in older patients who may benefit from the administration of S(+)-ketamine. ClinicalTrials.gov NCT05289050; https://clinicaltrials.gov/ct2/show/NCT05289050. DERR1-10.2196/53063.

Efficacy of Low Dose Intravenous Epinephrine Infusion in Improving Perioperative Outcomes in Patients Undergoing Transurethral Resection of Prostate: A Prospective Parallel Arm Double-Blind Randomized Control Trial

ObjectiveTo determine the efficacy of intraoperative low-dose intravenous epinephrine infusion in improving intraoperative bleeding and perioperative outcomes of TURP surgery. MethodsThis was a double-blinded, randomized control trial in which all patients undergoing bipolar TURP were included. Patients with uncontrolled hypertension, cardiac disease, and on anticoagulants were excluded. The study group received intravenous epinephrine, whereas the control group received normal saline at the same rate (0.05 μg/kg/min) throughout the procedure. Intraoperative blood loss was the primary outcome. The secondary outcomes were incidence of intraoperative hypotension (due to spinal anesthesia (SA)), resection time, indwelling catheter time, and length of hospitalization (LOH). ResultsThirty-six patients were included in each group. Demographic and clinical profiles were comparable with an overall median prostate size of 41 (34-52) gram in both groups. The primary objective, mean intraoperative blood loss in the study group was lower than the control group but statistically insignificant (67.91+/-18.7 ml vs 75.14+/-17.1 ml; p=0.086). Incidence of intraoperative hypotension was significantly lower in the study group (8.3% vs 33.3%; p= 0.01). Rest of the secondary outcomes, resection time (83 (64-111.5) min vs 86 (68-94.75) min; p=0.97), mean indwelling catheter time (p=0.94), postoperative complications (p=0.73), and LOH (p=0.87) were comparable. ConclusionsIn this first-of-its-kind trial, low-dose epinephrine infusion did not reduce intraoperative blood loss in patients undergoing TURP. However, it significantly reduced intraoperative hypotension, which complicates SA particularly in elderly population.

Left Ventricular Systolic‐Diastolic Coupling: Insight from Magnetic Resonance Dobutamine Stress

Left ventricular systolic and diastolic function are intrinsically linked, such that diastolic relaxation is influenced by the preceding systolic contraction – similar to how a springs recoil to its original shape is influenced by the degree of compression. Several clinical investigations have proposed quantifying the ratio between diastolic and systolic function to assess the coupling efficiency between the two, however, these cross‐sectional comparisons may be influenced by additional confounding factors, such as differences in tissue characteristics. Therefore, to extend our understanding, and directly examine the relationship between left ventricular systolic and diastolic coupling, we performed cardiac magnetic resonance imaging in six healthy volunteers (4F/2M, 22 ± 3 years, 24.4 ± 3.0 kg/m2) at rest and during low‐dose intravenous dobutamine infusion (2 µg/kg/min) to increase cardiac inotropy without affecting other, potentially confounding, regulators of diastolic function. Systolic and diastolic function was measured using gold‐standard tissue tagging, from three evenly spaced short axis images spanning the left ventricle from base to apex. As expected, dobutamine infusion increased peak circumferential strain (‐19.8 ± 1.6 % vs ‐21.3 ± 2.0 %, p = 0.002), systolic circumferential strain rate (CSRs: ‐96 ± 2 %/s vs ‐117 ± 7 %/s, p = 0.001), peak twist (8.2 ± 0.9 ° vs 10.7 ± 1.1 °, p = 0.002) and peak rate of systolic twist (TR: 40 ± 7 °/s vs 58 ± 8 °/s, p = 0.004). Independent of any changes in heart rate (59 ± 9 bpm vs 58 ± 9 bpm, p = 0.303) or end‐diastolic volume (171 ± 26 mL vs 170 ± 24 mL, p = 0.882), early diastolic circumferential strain rate (CSRd: 141 ± 15 %/s vs 163 ± 9 %/s, p = 0.019) and peak untwisting rate (UTR: ‐67 ± 24 °/s vs ‐88 ± 16 °/s, p = 0.018) subsequently increased. As a result, the ratio between diastolic and systolic measurements remained unchanged (CSRd/CSRs: 1.47 ± 0.14 vs 1.40 ± 0.15, p = 0.266; UTR/TR: 1.69 ± 0.54 vs 1.57 ± 0.37, p = 0.190). Taken together, these data support a growing body of evidence linking left ventricular systolic function with subsequent early diastolic relaxation and suggest that future investigations examining diastolic function should consider the influence of preceding systolic contractions.

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

Background & AimsHuman allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD).MethodsThis open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3.ResultsThe 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF.ConclusionsThe treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy.Clinical Trials RegistrationEudraCT 2016-001177-32.Lay summaryPatients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy.

Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000U, 3×daily). To assess the safety and efficacy of LDIVH in aSAH patients. We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9vs 18%; P=.004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

Commentary: Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage Is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Commentary: Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage Is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Effect of Intravenous Lidocaine on Postoperative Pain in Patients Undergoing Intraspinal Tumor Resection: Study Protocol for a Prospective Randomized Controlled Trial.

PurposePatients undergoing intraspinal tumor resection usually experience severe acute pain, delaying postoperative rehabilitation, and increasing incidence of chronic pain. Recently, an increasing number of studies have found that low-dose intravenous lidocaine infusion during and/or after surgery can reduce opioid usage and the incidence of related side effects, inhibit hyperalgesia and promote recovery. Thus far, no studies have evaluated the analgesic effect and safety of perioperative intravenous lidocaine infusion for intraspinal tumor resection, especially the long-term analgesic effects of patient-controlled analgesia (PCA) with lidocaine during the first postoperative 48 hours. This study tests the hypothesis that intra- and postoperative systemic lidocaine infusion for patients undergoing intraspinal tumor resection can relieve postoperative acute or chronic pain and reduce the opioid dosage and incidence of related side effects without other problems.Study Design and MethodsThis is a prospective, randomized, placebo-controlled, and double-blinded study. In total, 180 participants scheduled for intraspinal tumor resection will be randomly divided into lidocaine and placebo groups. The lidocaine group will be administered lidocaine intravenously during anesthesia and postoperative pain management during the first 48 postoperative hours; the placebo group will be administered normal saline at the same volume, infusion rate, and timing. The primary outcome will be the postoperative visual analog scale (VAS) score. Secondary outcomes will be postoperative cumulative sufentanil consumption, indicators of postoperative recovery, and the incidence of perioperative adverse events.DiscussionThis study investigates the effect of continuous intravenous lidocaine infusion on postoperative sufentanil consumption and VAS scores. The findings will provide a new strategy of anesthesia and analgesia management for intraspinal tumor resection.

Different dose regimes and administration methods of tranexamic acid in cardiac surgery: a meta-analysis of randomized trials

BackgroundThe efficacy of tranexamic acid (TXA) to reduce perioperative blood loss and allogeneic blood transfusion in cardiac surgeries has been proved in previous studies, but its adverse effects especially seizure has always been a problem of concern. This meta-analysis aims to provide information on the optimal dosage and delivery method which is effective with the least adverse outcomes.MethodsWe searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE for all relevant articles published before 2018/12/31. Inclusion criteria were adult patients undergoing elective heart surgeries, and only randomized control trials comparing TXA with placebo were considered. Two authors independently assessed trial quality and extracted relevant data.ResultsWe included 49 studies with 10,591 patients into analysis. TXA significantly reduced transfusion rate (RR 0.71, 95% CI 0.65 to 0.78, P<0.00001). The overall transfusion rate was 35%(1573/4477) for patients using TXA and 49%(2190/4408) for patients in the control group. Peri-operative blood loss (MD − 246.98 ml, 95% CI − 287.89 to − 206.06 ml, P<0.00001) and re-operation rate (RR 0.62, 95% CI 0.49 to 0.79, P<0.0001) were also reduced significantly. TXA usage did not increase risk of mortality, myocardial infarction, stroke, pulmonary embolism and renal dysfunction, but was associated with a significantly increase in seizure attack (RR 3.21, 95% CI 1.04 to 9.90, P = 0.04).The overall rate of seizure attack was 0.62%(21/3378) for patients using TXA and 0.15%(5/3406) for patients in the control group.In subgroup analysis, TXA was effective for both on-pump and off-pump surgeries. Topical application didn’t reduce the need for transfusion requirement, while intravenous delivery no matter as bolus injection alone or bolus plus continuous infusion were effective. Intravenous high-dose TXA didn’t further decrease transfusion rate compared with low-dose regimen, and increased the risk of seizure by 4.83 times. No patients in the low-dose group had seizure attack.ConclusionsTXA was effective in reducing transfusion requirement in all kinds of cardiac surgeries. Low-dose intravenous infusion was the most preferable delivery method which was as effective as high-dose regimen in reducing transfusion rate without increasing the risk of seizure.

Low-Dose Epinephrine Infusions and Tranexamic Acid During Lower-Extremity Total Joint Arthroplasty: Commentary on an article by Wei-Nan Zeng, MD, et al.: "Low-Dose Epinephrine Plus Tranexamic Acid Reduces Early Postoperative Blood Loss and Inflammatory Response. A Randomized Controlled Trial".

Low-Dose Epinephrine Infusions and Tranexamic Acid During Lower-Extremity Total Joint Arthroplasty: Commentary on an article by Wei-Nan Zeng, MD, et al.: "Low-Dose Epinephrine Plus Tranexamic Acid Reduces Early Postoperative Blood Loss and Inflammatory Response. A Randomized Controlled Trial".

Abstract 31: The INSPIRE trial: A randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity

Abstract Introduction: IRX-2 is a primary-cell-derived immune-restorative biologic consisting of a well-defined set of human cytokines that act on multiple immune system cell types to overcome tumor-mediated immunosuppression. The IRX-2 biologic stimulates T cells and natural killer cells and turns immature or defective dendritic cells into mature antigen-presenting cells. The IRX-2 biologic is provided as part of the IRX-2 regimen, which contains cyclophosphamide, indomethacin, and zinc to support an anticancer immune response. In a phase 2a clinical trial in 27 patients with therapy-naïve head and neck squamous cell carcinoma (HNSCC), treatment with the IRX-2 regimen was well tolerated and associated with immunologically mediated antitumor effects. The new multicenter randomized IRX-2 Neoadjuvant Therapy in Head and Neck SCC to Provide Immune Response Enhancement (INSPIRE) trial (NCT02609386) is designed to evaluate the safety and effectiveness of combined neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with oral cavity HNSCC, a disease known to have a disordered immune function. Study Design: Patients enrolled in INSPIRE must be at least 18 years of age; have previously untreated Stage II, III, or IVa SCC of the oral cavity that is surgically resectable with curative intent; and have a Karnofsky Performance status ≥70%. Up to 200 patients will be randomized 2:1 to either the IRX-2 biologic regimen arm or the IRX-2 regimen control arm (the IRX regimen minus the IRX-2 biologic). The neoadjuvant stage of INSPIRE begins 21 days before resection, when patients in both treatment arms will receive the IRX-2 regimen each day until resection. This regimen consists of the immunomodulatory chemotherapeutic agent cyclophosphamide, provided as a low-dose intravenous infusion, as well as two oral drugs, a zinc-containing multivitamin and indomethacin, a nonselective COX-1/COX-2 inhibitor. During this period, patients in the IRX-2 biologic regimen arm will also receive 10 days of the IRX-2 biologic subcutaneously injected into their bilateral sternocleidomastoid insertion regions. After resection, patients receive standard adjuvant radiation or chemoradiation therapy followed by adjuvant IRX-2 booster regimens at 3, 6, 9, and 12 months. During each 10-day booster period, patients in the IRX-2 biologic regimen arm also receive, for 5 consecutive days, the IRX-2 biologic subcutaneously injected into their bilateral deltoid regions. Study Endpoints: INSPIRE is now enrolling patients at 12 selected institutions in the United States. The primary endpoint of INSPIRE is event-free survival (EFS). Secondary endpoints include overall survival (OS) and safety as assessed by the incidence and severity of adverse events. Exploratory endpoints include changes in tumor size and histologic differences between pre- and post-treatment specimens in lymphocytic infiltration, assessed by both cell-surface marker expression (Perkin Elmer multiplex IHC) and immune cell gene signatures (NanoString). Conclusion: With enrollment of up to 200 patients, the randomized INSPIRE trial provides the opportunity to assess the ability of the IRX-2 regimen to improve EFS and OS by inhibiting tumor-mediated immunosuppression. Analysis of the exploratory endpoints will generate data to better describe the mechanism of action of the IRX-2 regimen and provide insight into the differences between inflammatory and non-inflammatory responses to SCCs of the oral cavity. Citation Format: Gregory T. Wolf, Mihir Patel, Audrey Erman, Jason G. Newman, Greg Krempl, Jorge Nieva, R. Bryan Bell, Michael Kaplan, Dennis Kraus, Jeffrey Moyer, Aru Panwar, Joseph Valentino. The INSPIRE trial: A randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 31.

Effects of intravenous low-dose dopamine infusion on glucose regulation during prolonged aerobic exercise.

The carotid body chemoreceptors are activated during hypoglycemia and contribute to glucoregulation during prolonged exercise in dogs. Low-dose intravenous infusions of dopamine have been shown to blunt the activation of the carotid body chemoreceptors during hypoxia. Therefore, we tested the hypotheses that dopamine would blunt glucoregulatory responses and attenuate plasma glucose during prolonged aerobic exercise in healthy participants. Twelve healthy participants completed two randomized exercise sessions at 65% peak oxygen consumption for up to 120 min. Saline was infused during one exercise session, and dopamine (2 μg·kg-1·min-1) was infused during the other session. Arterial plasma glucose, growth hormone, glucagon, cortisol, norepinephrine, and epinephrine were measured every 10 min. Exercise duration during dopamine infusion was 107 ± 6 and 119 ± 0.8 min during saline infusion. Glucose area under the curve during exercise was lower during dopamine (9,821 ± 686 vs. 11,194 ± 395 arbitrary units; P = 0.016). The ratio of circulating growth hormone to glucose and the ratio of glucagon to glucose were greater during dopamine ( P = 0.045 and 0.037, respectively). These results indicate that the infusion of dopamine during aerobic exercise impairs glucoregulation. This suggests that the carotid body chemoreceptors contribute to glucoregulation during prolonged exercise in healthy exercise-trained humans.

Effect of delayed onset prostacyclin on markers of endothelial function and damage after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a neurological emergency. Delayed ischemic neurological deficit is one of the main causes of poor outcome after SAH and is probably caused, at least in part, by cerebral vasospasm. The pathophysiology of this is multifaceted, but endothelial damage and activation as well as glycocalyx damage have been implicated. Prostacyclin has been shown to protect damaged and activated endothelium and to facilitate glycocalyx repair. We investigated biomarkers of endothelial activation and damage in patients with SAH randomized to 5days prostacyclin infusion or placebo. Patients with aneurysmal SAH managed by coiling or surgery, and a World Federation of Neurological Surgeons score between 1 and 4, and Fisher grade 3 or 4, were treated with a continuous low-dose intravenous prostacyclin infusion or placebo initiated on day 5 and discontinued on day 10 after SAH. Blood samples were drawn from the patients before, during and after prostacyclin/placebo infusion. Soluble biomarkers of endothelial cell activation (sE-selectin, sVE-cadherin) and damage (sTM), glycocalyx damage (syndecan-1) and sympathoadrenal activation (adrenaline, noradrenaline), were measured by ELISA. Ninety patients were randomized. Prostacyclin infusion influenced neither biomarkers of sympathoadrenal activation, endothelial activation and damage nor biomarkers of endothelial glycocalyx breakdown. We did not find any effects on markers of sympathoadrenal activation, endothelial damage and activation, or glycocalyx degradation of delayed onset prostacyclin infusion compared to placebo. Further trials investigating early onset endothelial repair using prostacyclin are warranted.

Low-dose intravenous ketamine for postcardiac surgery pain: Effect on opioid consumption and the incidence of chronic pain.

Background:Recent meta-analyses have concluded that low-dose intravenous ketamine infusions (LDKIs) during the postoperative period may help to decrease acute and chronic postoperative pain after major surgery.Aims:This study aims to evaluate the level of pain at least 3 months after surgery for patients treated with a postoperative LDKI versus patients who were not treated with a postoperative LDKI.Methods:Administrative and Ethics Board approval were obtained for this study. We performed a retrospective chart review for all patients receiving LDKI, and equal number of age-, sex-, and surgery-matched patients who did not receive LDKI. Low-dose ketamine was prepared using 100 mg of ketamine in 100 ml of normal saline and run between 50 and 200 mcg/kg/h.Results:We reviewed 115 patients with LDKI and 115 without LDKI. The average age was 63.1 years, 73% of the patients were men and sex was evenly distributed between LDKI and non-LDKI. The average duration of the ketamine infusions was 26.8 h with the average dose being 169.9 mg. At an average of 9 months after surgery, 42% of the ketamine group and 38% of the nonketamine group stated that they had had pain on discharge. Of these patients, 30% of the ketamine group and 26% of the nonketamine group still had pain at the time of the phone call. Women in both groups had more acute and chronic pain than men.Conclusion:These results show that LDKI does not promote a decrease in long-term postoperative pain.

Effects of alprazolam and cannabinoid-related compounds in an animal model of panic attack

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80μg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder.

Heparin infusion in simultaneous pancreas and kidney transplantation reduces graft thrombosis and improves graft survival.

Thrombosis of the pancreas after transplantation is the most common cause of relaparotomy and resultant graft loss. There is currently no standard protocol consistently proven to prevent thrombosis following transplantation. Our objective was to determine whether our protocol of post-operative low-dose intravenous (IV) heparin infusion would prevent graft thrombosis without additional complications in our patients. A total of 66 simultaneous pancreas kidney (SPK) transplants were performed at our institution from 2004 to 2014. Patients were divided into 2 retrospective cohort groups. Group 1 patients received only acetylsalicylic acid (ASA) 81mg/d started on post-operative day 1. Group 2 patients received IV heparin infusion beginning in the recovery room at a rate of 500IU/h for the first 24hours, reduced by 100IU/h every day to stop on day 5, and then received ASA 81mg/d afterward. Outcome and complication rates were compared between the two groups for 5years post-transplant. We observed a significant reduction in graft thrombosis and graft loss with (0/29) patients in the heparin group vs (7/33) 25.7% from the non-heparin (P<.01) with no differences in complication rates. We present a heparin infusion protocol which may help prevent graft thrombosis and graft loss in SPK transplantation.

Novel Treatments in Neuroprotection for Aneurysmal Subarachnoid Hemorrhage.

New neuroprotective treatments aimed at preventing or minimizing "delayed brain injury" are attractive areas of investigation and hold the potential to have substantial beneficial effects on aneurysmal subarachnoid hemorrhage (aSAH) survivors. The underlying mechanisms for this "delayed brain injury" are multi-factorial and not fully understood. The most ideal treatment strategies would have the potential for a pleotropic effect positively modulating multiple implicated pathophysiological mechanisms at once. My personal management (RFJ) of patients with aneurysmal subarachnoid hemorrhage closely follows those treatment recommendations contained in modern published guidelines. However, over the last 5years, I have also utilized a novel treatment strategy, originally developed at the University of Maryland, which consists of a 14-day continuous low-dose intravenous heparin infusion (LDIVH) beginning 12h after securing the ruptured aneurysm. In addition to its well-known anti-coagulant properties, unfractionated heparin has potent anti-inflammatory effects and through multiple mechanisms may favorably modulate the neurotoxic and neuroinflammatory processes prominent in aneurysmal subarachnoid hemorrhage. In my personal series of patients treated with LDIVH, I have found significant preservation of neurocognitive function as measured by the Montreal Cognitive Assessment (MoCA) compared to a control cohort of my patients treated without LDIVH (RFJ unpublished data presented at the 2015 AHA/ASA International Stroke Conference symposium on neuroinflammation in aSAH and in abstract format at the 2015 AANS/CNS Joint Cerebrovascular Section Annual Meeting). It is important for academic physicians involved in the management of these complex patients to continue to explore new treatment options that may be protective against the potentially devastating "delayed brain injury" following cerebral aneurysm rupture. Several of the treatment options included in this review show promise and could be carefully adopted as the level of evidence for each improves. Other proposed neuroprotective treatments like statins and magnesium sulfate were previously thought to be very promising and to varying degrees were adopted at numerous institutions based on somewhat limited human evidence. Recent clinical trials and meta-analysis have shown no benefit for these treatments, and I currently no longer utilize either treatment as prophylaxis in my practice.

Low-dose polymyxin: an option for therapy of Gram-negative sepsis.

Endotoxins are the major components of the outer membrane of most Gram-negative bacteria and are one of the main targets in inflammatory diseases. The presence of endotoxins in blood can provoke septic shock in case of pronounced immune response. Here we show in vitro inactivation of endotoxins by polymyxin B (PMB). The inflammatory activity of the LPS–PMB complex in blood was examined in vitro in freshly drawn blood samples. Plasma protein binding of PMB was determined by ultracentrifugation using membranes with different molecular cut-offs, and PMB clearance during dialysis was calculated after in vitro experiments using the AV1000S filter. The formed LPS–PMB complex has lower inflammatory activity in blood, which results in highly reduced cytokine secretion. According to in vitro measurements, the appropriate plasma level of PMB for LPS inactivation is between 100 and 200 ng/ml. Furthermore, the combination of cytokine removal by adsorbent treatment with LPS inactivation by PMB dosage leads to strong suppression of inflammatory effects in blood in an in vitro model. Inactivation of endotoxins by low-dose intravenous PMB infusion or infusion into the extracorporeal circuit during blood purification can be applied to overcome the urgent need for endotoxin elimination not only in treatment of sepsis, but also in liver failure.